Unravelling novel molecular mechanisms underlying vascular cell differentiation from stem/progenitor cells
One of our main research interests is specifically focussed on the study of identifying novel targets/molecules and/or signalling pathways, such as microRNAs, transcription factors, and other molecules, which are crucial for vascular endothelial cell (EC) and smooth muscle cell (SMC) differentiation from murine/human pluripotent stem cells (ESCs: embryonic stem cells; iPSCs: induced pluripotent stem cells) as well as adult stem/progenitor cells including blood vessel wall stem cells. By establishing a simple but very efficient vascular cell differentiation model(s), we are the first to report that matrix protein Collagen-IV, Nox4, Nrf3, Pla2g7, HDAC3, HDAC7, Cbx3, hnRNPA1, hnRNPA2B1, microRNA-34a, and miR-22 play a regulatory role in vascular cell differentiation from ESCs or adult stem/progenitor cells. We will continue exploring the underlying signal pathways of vascular cell differentiation from murine/human iPSCs, and its implications in vascular diseases. Our findings provide useful mechanistic insights into stem cell differentiation toward vascular endothelial cells and smooth muscle cells, and could significantly enhance the knowledge of stem cell biology and vascular biology, such as stem cell differentiation and self-renewal, vasculogenesis, angiogenesis, and vascular repair.
Stem/progenitor cells (SPCs) and cardiovascular diseases (CVD)
Atherosclerosis is the underlying cause of CVDs. Growing evidence indicates that SPCs play a crucial role in the development of atherosclerosis and heart disease. Using various mouse models and human tissue samples, we are studying the contribution of SPCs to the pathogenesis of atherosclerosis, uncovering the novel mechanisms of SPC differentiation into endothelial and smooth muscle cells, and investigating a potential use of stem cell therapy for vascular disease.
Identifying and exploring the potential novel therapeutic targets for cardiovascular diseases
CVD is still the number one killer. Accumulating evidence indicates that different proteases such as matrix metalloproteinases (MMPs) and neutrophil elastase (NE) play an important and distinct role in the development of atherosclerotic lesions and atheromatous plaque rupture. However, its functional role and underlying molecular mechanism remain to be explored. Our group have become very focused on the investigating the underlying molecular mechanisms of SPC migration into atherosclerotic lesion and its relevance in the development of vascular diseases. We have recently demonstrated for the first time that MMP8 plays a causal role in atherosclerosis and neointima SMC hyperplasia, and that MMP8 possesses a divergent and regulatory role in SPC migration into atherosclerotic lesions, angiogenesis, and macrophage differentiation/polarisation. Moreover, by using various animal models of cardiovascular diseases, we are exploring if the identified genes/molecules (e.g. miR-34a, miR-22, Nrf3, and hnRNPA1) from our abovementioned stem cell differentiation studies represent a novel therapeutic target for cardiovascular diseases.
Cellular reprogramming and cardiovascular regeneration
Cellular reprogramming of somatic cells into pluripotent stem cells or other somatic cells has opened the new avenues of biomedical research and regenerative medicine. Endothelium dysfunction or damage is a hallmark of the onset of vascular diseases, and cell therapy strategies that aim to rapidly repair and restore vascular function are being increasingly explored as viable therapeutic avenues. Development of fast and robust new methodologies that produce well-characterised, homogenous, clinical-grade cells suitable for tissue repair/re-modelling would have great utility. One of our most recent research projects will be studying if the identified vascular cell differentiation genes from our stem cell studies could directly reprogram other somatic cells into functional vascular ECs and SMCs, and their therapeutic potential in vascular diseases.
Functional involvements of Non-coding RNAs in stem cell fate decision and vascular diseases
Recently, growing evidence has suggested that non-coding RNAs including microRNAs and long non-coding RNAs play crucial roles in embryonic development and various diseases. Thus, we are also interested in the significance of these molecules in stem cell pluripotency and vascular cell specifications, and their application in the prevention of vascular diseases.
Figures:
During stem cell differentiation, instinct signal pathways composed of multiple genes are activated and by extinct stimuli/signalling pathways such as endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) and/or auto-secreted growth factors (TGFβ1 and VEGF), respectively. After activation/up-regulation, they trigger/initiate vascular endothelial or smooth muscle cell differentiation. Stem cell-derived endothelial cells are the ideal cellular source for cardiovascular regeneration and engineered vascular grafts. Newly identified SMC differentiation regulators (e.g. miR-22, miR-34a, hnRNPA1, Cbx3) are the potential therapeutic targets for cardiovascular diseases (e.g. angioplasty-induced restenosis and atherosclerosis).
We are the first to confirm a causal effect for matrix metalloproteinase-8 (MMP8) in atherosclerosis. MMP8 controls atherosclerosis through 1) converting Angiotensin I (Ang I) to Ang II, which in turn regulates VCAM-1 in endothelium and increases recruitment of leukocytes into vascular wall, leading to vascular inflammation and atherosclerosis progression (Circ Res. 2009); 2) up-regulating CD31 in endothelial cells and augmenting atherosclerotic angiogenesis (Cardiovasc Res. 2013); 3) increasing bone marrow-derived stem/progenitor cell mobilisation into atherosclerotic plaque by cleaving ADAM10 and E-cadherin (Circ Res. 2013); 4) promoting angioplasty-induced restenosis by controlling smooth muscle cell behaviours (Arterioscler Thromb Vasc Biol., 2014); and 5) modulating macrophage differentiation & polarisation (J Biol Chem. 2015). Recently, we have demonstrated that another proteinase, Neutrophil Elastase (NE), also promotes atherosclerosis (J Am Heart Assoc. 2018), and we are currently investigating the underlying cellular & molecular mechanisms of atherosclerosis controlled by NE.
